Kirill Neklyudov

While score-based generative models are the model of choice across diverse domains, there are limited tools available for controlling infere… (see more)nce-time behavior in a principled manner, e.g. for composing multiple pretrained models. Existing classifier-free guidance methods use a simple heuristic to mix conditional and unconditional scores to approximately sample from conditional distributions. However, such methods do not approximate the intermediate distributions, necessitating additional 'corrector' steps. In this work, we provide an efficient and principled method for sampling from a sequence of annealed, geometric-averaged, or product distributions derived from pretrained score-based models. We derive a weighted simulation scheme which we call Feynman-Kac Correctors (FKCs) based on the celebrated Feynman-Kac formula by carefully accounting for terms in the appropriate partial differential equations (PDEs). To simulate these PDEs, we propose Sequential Monte Carlo (SMC) resampling algorithms that leverage inference-time scaling to improve sampling quality. We empirically demonstrate the utility of our methods by proposing amortized sampling via inference-time temperature annealing, improving multi-objective molecule generation using pretrained models, and improving classifier-free guidance for text-to-image generation. Our code is available at https://github.com/martaskrt/fkc-diffusion.

2025-03-04

ArXiv (preprint)

Feynman-Kac Correctors in Diffusion: Annealing, Guidance, and Product of Experts

Marta Skreta

Tara Akhound-Sadegh

Viktor Ohanesian

Roberto Bondesan

Alan Aspuru-Guzik

Arnaud Doucet

Rob Brekelmans

Alexander Tong

While score-based generative models are the model of choice across diverse domains, there are limited tools available for controlling infere… (see more)nce-time behavior in a principled manner, e.g. for composing multiple pretrained models. Existing classifier-free guidance methods use a simple heuristic to mix conditional and unconditional scores to approximately sample from conditional distributions. However, such methods do not approximate the intermediate distributions, necessitating additional 'corrector' steps. In this work, we provide an efficient and principled method for sampling from a sequence of annealed, geometric-averaged, or product distributions derived from pretrained score-based models. We derive a weighted simulation scheme which we call Feynman-Kac Correctors (FKCs) based on the celebrated Feynman-Kac formula by carefully accounting for terms in the appropriate partial differential equations (PDEs). To simulate these PDEs, we propose Sequential Monte Carlo (SMC) resampling algorithms that leverage inference-time scaling to improve sampling quality. We empirically demonstrate the utility of our methods by proposing amortized sampling via inference-time temperature annealing, improving multi-objective molecule generation using pretrained models, and improving classifier-free guidance for text-to-image generation. Our code is available at https://github.com/martaskrt/fkc-diffusion.

2025-03-04

ArXiv (preprint)

Meta Flow Matching: Integrating Vector Fields on the Wasserstein Manifold

Lazar Atanackovic

Xi Zhang

Brandon Amos

Mathieu Blanchette

Leo J Lee

Yoshua Bengio

Alexander Tong

Numerous biological and physical processes can be modeled as systems of interacting entities evolving continuously over time, e.g. the dynam… (see more)ics of communicating cells or physical particles. Learning the dynamics of such systems is essential for predicting the temporal evolution of populations across novel samples and unseen environments. Flow-based models allow for learning these dynamics at the population level - they model the evolution of the entire distribution of samples. However, current flow-based models are limited to a single initial population and a set of predefined conditions which describe different dynamics. We argue that multiple processes in natural sciences have to be represented as vector fields on the Wasserstein manifold of probability densities. That is, the change of the population at any moment in time depends on the population itself due to the interactions between samples. In particular, this is crucial for personalized medicine where the development of diseases and their respective treatment response depends on the microenvironment of cells specific to each patient. We propose Meta Flow Matching (MFM), a practical approach to integrating along these vector fields on the Wasserstein manifold by amortizing the flow model over the initial populations. Namely, we embed the population of samples using a Graph Neural Network (GNN) and use these embeddings to train a Flow Matching model. This gives MFM the ability to generalize over the initial distributions unlike previously proposed methods. We demonstrate the ability of MFM to improve prediction of individual treatment responses on a large scale multi-patient single-cell drug screen dataset.

2025-01-22

ICLR.cc/2025/Conference (poster)

openreview.net

The Superposition of Diffusion Models Using the Itô Density Estimator

Marta Skreta

Lazar Atanackovic

Joey Bose

Alexander Tong

The Cambrian explosion of easily accessible pre-trained diffusion models suggests a demand for methods that combine multiple different pre-t… (see more)rained diffusion models without incurring the significant computational burden of re-training a larger combined model. In this paper, we cast the problem of combining multiple pre-trained diffusion models at the generation stage under a novel proposed framework termed superposition. Theoretically, we derive superposition from rigorous first principles stemming from the celebrated continuity equation and design two novel algorithms tailor-made for combining diffusion models in SuperDiff. SuperDiff leverages a new scalable It\^o density estimator for the log likelihood of the diffusion SDE which incurs no additional overhead compared to the well-known Hutchinson's estimator needed for divergence calculations. We demonstrate that SuperDiff is scalable to large pre-trained diffusion models as superposition is performed solely through composition during inference, and also enjoys painless implementation as it combines different pre-trained vector fields through an automated re-weighting scheme. Notably, we show that SuperDiff is efficient during inference time, and mimics traditional composition operators such as the logical OR and the logical AND. We empirically demonstrate the utility of using SuperDiff for generating more diverse images on CIFAR-10, more faithful prompt conditioned image editing using Stable Diffusion, as well as improved conditional molecule generation and unconditional de novo structure design of proteins. https://github.com/necludov/super-diffusion

2024-12-23

ArXiv (preprint)

Doob's Lagrangian: A Sample-Efficient Variational Approach to Transition Path Sampling

Yuanqi Du

Michael Plainer

Rob Brekelmans

Chenru Duan

Frank No'e

Carla P. Gomes

Alan Aspuru-Guzik

Rare event sampling in dynamical systems is a fundamental problem arising in the natural sciences, which poses significant computational cha… (see more)llenges due to an exponentially large space of trajectories. For settings where the dynamical system of interest follows a Brownian motion with known drift, the question of conditioning the process to reach a given endpoint or desired rare event is definitively answered by Doob's h-transform. However, the naive estimation of this transform is infeasible, as it requires simulating sufficiently many forward trajectories to estimate rare event probabilities. In this work, we propose a variational formulation of Doob's h-transform as an optimization problem over trajectories between a given initial point and the desired ending point. To solve this optimization, we propose a simulation-free training objective with a model parameterization that imposes the desired boundary conditions by design. Our approach significantly reduces the search space over trajectories and avoids expensive trajectory simulation and inefficient importance sampling estimators which are required in existing methods. We demonstrate the ability of our method to find feasible transition paths on real-world molecular simulation and protein folding tasks.

2024-10-10

ArXiv (preprint)

Doob's Lagrangian: A Sample-Efficient Variational Approach to Transition Path Sampling

Yuanqi Du

Michael Plainer

Rob Brekelmans

Chenru Duan

Frank No'e

Carla P. Gomes

Alan Aspuru-Guzik

Rare event sampling in dynamical systems is a fundamental problem arising in the natural sciences, which poses significant computational cha… (see more)llenges due to an exponentially large space of trajectories. For settings where the dynamical system of interest follows a Brownian motion with known drift, the question of conditioning the process to reach a given endpoint or desired rare event is definitively answered by Doob's h-transform. However, the naive estimation of this transform is infeasible, as it requires simulating sufficiently many forward trajectories to estimate rare event probabilities. In this work, we propose a variational formulation of Doob's h-transform as an optimization problem over trajectories between a given initial point and the desired ending point. To solve this optimization, we propose a simulation-free training objective with a model parameterization that imposes the desired boundary conditions by design. Our approach significantly reduces the search space over trajectories and avoids expensive trajectory simulation and inefficient importance sampling estimators which are required in existing methods. We demonstrate the ability of our method to find feasible transition paths on real-world molecular simulation and protein folding tasks.

2024-10-01

arXiv (published)

A Computational Framework for Solving Wasserstein Lagrangian Flows

Rob Brekelmans

Alexander Tong

Lazar Atanackovic

Qiang Liu

Alireza Makhzani

The dynamical formulation of the optimal transport can be extended through various choices of the underlying geometry (kinetic energy), and … (see more)the regularization of density paths (potential energy). These combinations yield different variational problems (Lagrangians), encompassing many variations of the optimal transport problem such as the Schr\"odinger bridge, unbalanced optimal transport, and optimal transport with physical constraints, among others. In general, the optimal density path is unknown, and solving these variational problems can be computationally challenging. We propose a novel deep learning based framework approaching all of these problems from a unified perspective. Leveraging the dual formulation of the Lagrangians, our method does not require simulating or backpropagating through the trajectories of the learned dynamics, and does not need access to optimal couplings. We showcase the versatility of the proposed framework by outperforming previous approaches for the single-cell trajectory inference, where incorporating prior knowledge into the dynamics is crucial for correct predictions.

2024-07-08

Proceedings of the 41st International Conference on Machine Learning (published)

Efficient Evolutionary Search Over Chemical Space with Large Language Models

Haorui Wang

Marta Skreta

Cher Tian Ser

Wenhao Gao

Lingkai Kong

Felix Streith-Kalthoff

Chenru Duan

Yuchen Zhuang

Yue Yu

Yanqiao Zhu 0001

Yuanqi Du

Alan Aspuru-Guzik

Chao Zhang

Molecular discovery, when formulated as an optimization problem, presents significant computational challenges because optimization objectiv… (see more)es can be non-differentiable. Evolutionary Algorithms (EAs), often used to optimize black-box objectives in molecular discovery, traverse chemical space by performing random mutations and crossovers, leading to a large number of expensive objective evaluations. In this work, we ameliorate this shortcoming by incorporating chemistry-aware Large Language Models (LLMs) into EAs. Namely, we redesign crossover and mutation operations in EAs using LLMs trained on large corpora of chemical information. We perform extensive empirical studies on both commercial and open-source models on multiple tasks involving property optimization, molecular rediscovery, and structure-based drug design, demonstrating that the joint usage of LLMs with EAs yields superior performance over all baseline models across single- and multi-objective settings. We demonstrate that our algorithm improves both the quality of the final solution and convergence speed, thereby reducing the number of required objective evaluations. Our code is available at http://github.com/zoom-wang112358/MOLLEO

2024-06-23

ArXiv (preprint)

Meta Flow Matching: Integrating Vector Fields on the Wasserstein Manifold

Lazar Atanackovic

Xi Zhang

Brandon Amos

Mathieu Blanchette

Leo J Lee

Yoshua Bengio

Alexander Tong

Numerous biological and physical processes can be modeled as systems of interacting samples evolving continuously over time, e.g. the dynami… (see more)cs of communicating cells or physical particles. Flow-based models allow for learning these dynamics at the population level --- they model the evolution of the entire distribution of samples. However, current flow-based models are limited to a single initial population and a set of predefined conditions which describe different dynamics. We propose

2024-06-17

ICML.cc/2024/Workshop/GRaM (published)

openreview.net

Efficient Evolutionary Search Over Chemical Space with Large Language Models

Haorui Wang

Marta Skreta

Cher Tian Ser

Wenhao Gao

Lingkai Kong

Felix Streith-Kalthoff

Chenru Duan

Yuchen Zhuang

Yue Yu

Yanqiao Zhu 0001

Yuanqi Du

Alan Aspuru-Guzik

Chao Zhang

Molecular discovery, when formulated as an optimization problem, presents significant computational challenges because optimization objectiv… (see more)es can be non-differentiable. Evolutionary Algorithms (EAs), often used to optimize black-box objectives in molecular discovery, traverse chemical space by performing random mutations and crossovers, leading to a large number of expensive objective evaluations. In this work, we ameliorate this shortcoming by incorporating chemistry-aware Large Language Models (LLMs) into EAs. Namely, we redesign crossover and mutation operations in EAs using LLMs trained on large corpora of chemical information. We perform extensive empirical studies on both commercial and open-source models on multiple tasks involving property optimization, molecular rediscovery, and structure-based drug design, demonstrating that the joint usage of LLMs with EAs yields superior performance over all baseline models across single- and multi-objective settings. We demonstrate that our algorithm improves both the quality of the final solution and convergence speed, thereby reducing the number of required objective evaluations. Our code is available at http://github.com/zoom-wang112358/MOLLEO

2024-06-01

arXiv (published)

Diffusion Models as Constrained Samplers for Optimization with Unknown Constraints

Lingkai Kong

Yuanqi Du

Wenhao Mu

Valentin De Bortol

Haorui Wang

Dongxia Wu

Aaron Ferber

Yi-An Ma

Carla P. Gomes

Chao Zhang

Addressing real-world optimization problems becomes particularly challenging when analytic objective functions or constraints are unavailabl… (see more)e. While numerous studies have addressed the issue of unknown objectives, limited research has focused on scenarios where feasibility constraints are not given explicitly. Overlooking these constraints can lead to spurious solutions that are unrealistic in practice. To deal with such unknown constraints, we propose to perform optimization within the data manifold using diffusion models. To constrain the optimization process to the data manifold, we reformulate the original optimization problem as a sampling problem from the product of the Boltzmann distribution defined by the objective function and the data distribution learned by the diffusion model. Depending on the differentiability of the objective function, we propose two different sampling methods. For differentiable objectives, we propose a two-stage framework that begins with a guided diffusion process for warm-up, followed by a Langevin dynamics stage for further correction. For non-differentiable objectives, we propose an iterative importance sampling strategy using the diffusion model as the proposal distribution. Comprehensive experiments on a synthetic dataset, six real-world black-box optimization datasets, and a multi-objective molecule optimization dataset show that our method achieves better or comparable performance with previous state-of-the-art baselines.

2024-02-01

arXiv (published)

Structured Inverse-Free Natural Gradient Descent: Memory-Efficient & Numerically-Stable KFAC

Wu Lin

Felix Dangel

Runa Eschenhagen

Agustinus Kristiadi

Richard E. Turner

Alireza Makhzani

Second-order methods such as KFAC can be useful for neural net training. However, they are often memory-inefficient since their precondition… (see more)ing Kronecker factors are dense, and numerically unstable in low precision as they require matrix inversion or decomposition. These limitations render such methods unpopular for modern mixed-precision training. We address them by (i) formulating an inverse-free KFAC update and (ii) imposing structures in the Kronecker factors, resulting in structured inverse-free natural gradient descent (SINGD). On modern neural networks, we show that SINGD is memory-efficient and numerically robust, in contrast to KFAC, and often outperforms AdamW even in half precision. Our work closes a gap between first- and second-order methods in modern low-precision training.

2024-01-01

ICML (published)

proceedings.mlr.press